UNLABELLED: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. AIMS: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. RESULTS: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. INNOVATION: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. CONCLUSION: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.
UNLABELLED: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. AIMS: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. RESULTS: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. INNOVATION: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. CONCLUSION: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.
Authors: A Serrano-Mollar; D Closa; N Prats; S Blesa; M Martinez-Losa; J Cortijo; J M Estrela; E J Morcillo; O Bulbena Journal: Br J Pharmacol Date: 2003-03 Impact factor: 8.739
Authors: F Takahashi; K Takahashi; T Okazaki; K Maeda; H Ienaga; M Maeda; S Kon; T Uede; Y Fukuchi Journal: Am J Respir Cell Mol Biol Date: 2001-03 Impact factor: 6.914
Authors: M Ushio-Fukai; L Hilenski; N Santanam; P L Becker; Y Ma; K K Griendling; R W Alexander Journal: J Biol Chem Date: 2001-10-03 Impact factor: 5.157
Authors: Ramon Bataller; Robert F Schwabe; Youkyung H Choi; Liu Yang; Yong Han Paik; Jeffrey Lindquist; Ting Qian; Robert Schoonhoven; Curt H Hagedorn; John J Lemasters; David A Brenner Journal: J Clin Invest Date: 2003-11 Impact factor: 14.808
Authors: Richard P Marshall; Peter Gohlke; Rachel C Chambers; David C Howell; Steve E Bottoms; Thomas Unger; Robin J McAnulty; Geoffrey J Laurent Journal: Am J Physiol Lung Cell Mol Physiol Date: 2003-05-16 Impact factor: 5.464
Authors: Eric S White; Victor J Thannickal; Shannon L Carskadon; Emily G Dickie; Donna L Livant; Sonja Markwart; Galen B Toews; Douglas A Arenberg Journal: Am J Respir Crit Care Med Date: 2003-06-05 Impact factor: 21.405